Pseudodipeptide Inhibitors of Protein Farnesyltransferase

Article abstract of DOI:10.1021/jm00020a010

A series of pseudodipeptide amides are described that inhibit Ras protein farnesyltransferase (PFTase).These inhibitors are truncated versions of the C-terminal tetrapeptide (CAAX motif) of Ras that serves as the signal sequence for PFTase-catalyzed protein farnesylation.In contrast to CAAX peptidomimetics previously reported, these inhibitors do not have a C-terminal carboxyl moiety, yet they inhibit farnesylation in vitro at < 100 nM.Despite the absence of the X residue in the CAAX motif, which normally directs prenylation specificity, these pseudodipeptides are greater than 100-fold selective for PFTase over type 1 protein geranylgeranyltransferase.